Bone voids alternatively referred to as bone defects are commonly caused by injury, disease, or surgical interventions. Bone fractures caused mostly by trauma to a bone as well as jaw bone damages caused by trauma, disease or tooth loss are those most commonly associated with bone infections. Early efforts must be made to decontaminate the bones and the surrounding soft tissues and to stabilize the bone void site in order to enable successful bone healing. Unfortunately, the rate and severity of bone infections following such bone void defects is high. Infection is a particularly severe complication of an open fracture and the higher Gustilo types have been shown to have high incidence of this complication. Type-IIIB and type IIIC open fractures have been described as the most critical injuries with as high as 48% of deep bony infections after Type-IIIB fractures. The current oral and intravenous antibiotic treatment allows high concentrations of antibiotics in the blood, but often insufficient local concentration of the drug at the bone voids and specifically in contaminated or infected bone voids defects. Local antibiotic administration is commonly used to overcome poor bone penetration of antibiotic given systemically (intravenously or orally). The first product on the market for local treatment of infected bone is based on antibiotics loaded in poly(methylmethacrylate) (PMMA) bone cement, in the form of antibiotic beads (Osetermann et al., J. Bone and Joint Surgery, 1995, 77B(1):93-97). However, the clinical effect of using this method is hampered by the fact that >90% of the drug remained trapped inside the cement beads. Furthermore, bone cement is not biodegradable and is not osteoconductive, and therefore has to be removed by a second surgical procedure.
Biodegradable polymers such as polylactic/polyglycolide (PLGA), chitosan or collagen were also used as antibiotic-saturated implants in bone lesions. However, such polymeric drug delivery systems cannot maintain a constant and sufficient release rate of antibiotics over the prolonged period of time needed to fully eradicate the invading bacteria. Moreover, the polymeric systems cannot support osteoconductive bone in growth into the void. To overcome these major limitations, antibiotics were added to osteoconductive bone fillers such as calcium sulfate hemihydrate pellets, tricalcium phosphate (TCP) and to calcium hydroxyapatite ceramics. In these bone fillers the release of antibiotics is characterized by a rapid release of the drug in the first week, followed by a sharp decrease in the amounts released after that.
An alternative approach for treating bone infection/bone destruction is using a liposomal drug delivery system to release antibiotics. Liposomes offer a safe and convenient way to control the rate and the location of the delivered drug. But this requires prolonged and repeated systemic applications of the encapsulated drugs in order to achieve complete sterilization of bone and soft tissues. When liposomal antibiotics were combined with osteoconductive elements, most of the drug (˜60%) was released in the first 24 h, followed by decreasing amounts in the following days. Thus, the current local delivery systems available do not provide sustainable high local antibiotic concentration at the fracture site during the healing process. Therefore, in spite of the addition of systemic antibiotic treatment with these local treatments, they cannot fully eradicate the bacterial infection in most patients.
Osteoset-T® and PerOssal® are approved biodegradable bone fillers, based on TCP granules, and are used for filling or reconstruction of bone defects in orthopedics, orthodontic and facial surgery. In addition to their osteoconductive properties, these products can also release antibiotics locally, and they are therefore used in infected wounds and in bone defects. Their biodegradability and osteoconductivity suggest a significant advantage over PMMA beads. However, their high burst and the short release period of the drug (antibiotic), for no more than several days following the implantation, represent significant limit to their anti-bacterial effect.
WO 2010/007623 to one of the inventors of the present invention and others provides compositions for extended release of an active ingredient, comprising a lipid-saturated matrix formed from a biodegradable polymer. The present invention also provides methods of producing the matrix compositions and methods for using the matrix compositions to provide controlled release of an active ingredient in the body of a subject in need thereof. These drug delivery matrices provided extended release of the active agent over a period of days, weeks or months.
There is an unmet medical need for effective means for the treatment of bone fractures, and in particular open bone fractures, which promote the bone healing process while preventing infection in a single treatment.